C-X-C chemokine receptor type 4 (CXCR4), also known as fusing or cluster of differentiation 184 (CD184), is a seven transmembrane G-protein coupled receptor (GPCR) belonging to the Class I GPCR or rhodopsin-like GPCR family. Stromal-derived-factor-1 (SDF-1) or C-X-C chemokine ligand 12 (CXCL12) is the major ligand of CXCR4 and the interaction recognition between CXCL12 and CXCR4 recruits cells to the organ sites with high levels of CXCL12 expression. The CXCL12/CXCR4 axis has been shown to be involved in a number of pathological conditions, including cancer and inflammation. CXCR4 plays a role as a homing receptor to the lymph nodes, lung, liver, and bone. Homing, the mechanism that allows foreign tissue-origin cells to reside and proliferate, is believed to be the rate-limiting step of the multi-step metastatic process. CXCR4 is overexpressed in many human cancer types, such as breast, leukemia, lung, and prostate cancers.
Inflammation is inextricably associated with primary tumor progression and contributes to metastatic outgrowth in distant organs. The COX pathway has long been used as the major target for anti-inflammatory drugs. Both traditional non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors exhibit their anti-inflammatory activity by inhibiting COX-2. Nevertheless, the prolonged use of traditional anti-inflammatory drugs is associated with potential serious side effects such as kidney failure, ulcers and prolonged bleeding after an injury or surgery. Furthermore, rofecoxib and valdecoxib were withdrawn from the market due to an increased risk of cardiovascular complications.
Accumulating evidence suggests the involvement of CXCR4-CXCL12 interaction in various inflammatory diseases, including rheumatoid arthritis, autoimmune diseases, ischemic injuries, inflammatory bowel disease, and pneumonia. Based on these findings, development of inhibitors blocking CXCR4 presents a new avenue for complementary therapeutic strategy in inflammatory diseases as well as cancer.
AMD3100 is a CXCR4 inhibitor approved by FDA for stem cell mobilization. Although it benefits patients with certain diseases, long term treatment can introduce lung and liver fibrosis. Hence there is a need to develop improved CXCR4 inhibitors.
Mooring et al. report pyridine derivatives as potential antagonists of chemokine receptor type 4, Heterocyclic communications, 2014, 20(3): 149-153. Zhu et al. report dipyrimidine amines as chemokine receptor type 4 antagonists. J. Med. Chem., 53 (2010), pp. 8556-8568. See also Zhan et al., J. Med. Chem., 50 (2007), pp. 5655-5664, U.S. Pat. No. 8,008,312 and 8,114,884.
Liang et al. report a small molecule modulator of CXCR4. PLoS One 2012, 7 (4), e34038.
Bai et al. report symmetrical bis-tertiary amines as CXCR4 inhibitors. Eur J Med Chem 2016, 118, 340-350.
Mishra et al. report characterization of CXCR4 receptor agonists and antagonists. Sci. Rep., 2016, 6, 30155
References cited herein are not an admission of prior art.